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Cevostamab Cevostamab is a humanized, IgG-based T cell binding bispecific antibody that targets FcRH5 (Fc receptor homolog 5) on the surface of myeloma cells and CD3 on the surface of T cells to form effective immune synapses.
This activates T cells to kill myeloma cells
.
At the 2020 ASH Annual Meeting (#292, #3213), Roche announced for the first time that Cevostamab has shown encouraging activity in multi-line treatment of patients with relapsed/refractory multiple myeloma (RRMM) (GO39775, phase I clinical trial) )
.
The relevant results of the study (EHA-EP965) will be updated again at this EHA annual meeting
.
Research background Almost all MM patients will eventually relapse after initial treatment or salvage treatment1, and there is still a need to study new targets and treatment methods
.
FcRH5 is a type I membrane protein containing an Ig domain and is only expressed in the B cell lineage 2-4
.
The FcRH5 gene is located near the chromosomal breakpoint in 1q21.
4.
Previous studies have shown that the expression rate of FcRH5 on myeloma cells is close to 100%, and the expression rate on myeloma cells is higher than that of normal B cells4
.
Cevostamab is an IgG-based humanized bispecific antibody that binds to the proximal membrane domain of FcRH5 on myeloma cells and CD3 on T cells4
.
Double binding promotes T cell activation and effectively kills myeloma cells4
.
Preliminary data in the dose escalation phase of the ongoing phase I study (GO39775; NCT03275103) indicate that cevostamab monotherapy has controllable toxicity and promising activity in patients with advanced RRMM5
.
In the current analysis, we analyzed the relationship between baseline FcRH5 expression and baseline patient disease characteristics in the GO39775 study, as well as the relationship between baseline FcRH5 expression and response to Cevostamab treatment
.
01 Mainly included in the standard RRMM that is invalid or intolerant to existing treatments; ECOG 0-1; those who have previously received chimeric antigen receptor T cells (CAR-T), bispecific antibodies or antibody-drug conjugates (ADC) Patients can be included in 02Cevostamab dosage and usage (see figure below) Q3W IV, to disease progression or intolerance, the current maximum of 17 cycles is to reduce cytokine release syndrome (CRS), the first cycle (C1) uses a single fraction Step-by-step administration, preventive use of acetaminophen, diphenhydramine, and corticosteroids; only C1 requires hospitalization infusion 03 Primary endpoint of the study: safety and tolerability (MTD, DLTs), phase II recommended dose (RP2D) Secondary endpoint: Expression of the biomarker FcRH5, an activity, pharmacodynamic and pharmacokinetic biomarker, on myeloma cells by flow cytometry and a molecule expressed as an equivalent soluble fluorescent dye (MESF) before treatment with Cevostatab The collected bone marrow aspirate was evaluated
.
The expression of FcRH5 was analyzed hierarchically according to the number of previous treatment lines, treatment types, and cytogenetic abnormalities
.
Cytogenetic abnormalities refer to high-risk (one or more of the following abnormalities: 1q21 gain, t(4;14), t(14;16)), or del(17p)) and standard risk cytogenetics
.
At the end of the study results data (August 18, 2020), 53 patients were enrolled in the study, with a median age of 62 years (33-80 years), a median number of treatment lines (2-15), and 100% had received PIs Treatment, 100% received IMiDs treatment, 81% received anti-CD38 monoclonal antibody (anti-CD38 mAb) treatment, 72% of the patients were refractory to 3 drugs (≥1 PI, ≥1 IMiD, ≥1 anti-CD38 mAb), 94% of patients did not respond to the last treatment
.
28 out of 53 patients had cytogenetic high-risk markers (high-risk genetics, including: 1q21, t(4;14), t(14;16) or del(17p))
.
The ORR in the population ≥ 3.
6/20 mg was 53%, and the ORR was at the active dose level and above, and was stratified according to the number of previous treatment lines to maintain a consistent level
.
In all patients with evaluable biomarkers, FcRH5 expression on myeloma cells was observed; no significant relationship between the response to Cevostamab and the baseline FcRH5 expression level was observed at the active dose level
.
FcRH5 expression does not seem to be affected by the number of previous treatment lines and treatments.
FcRH5 expression may increase in patients with cytogenetic abnormalities, but more data are still needed for further confirmation
.
Among the patients whose biomarkers can be evaluated, 28 can provide cytogenetic information, of which 25 are high-risk and 3 are standard risk
.
The MESF fluorescence value was 8839 (2137-32381, n=9) in patients with two cytogenetic abnormalities, and 5379 (352-44409, n=16) in patients with one cytogenetic abnormality.
The number of patients with abnormal cytogenetics was 2591 (766-4560, n=3)
.
The median MESF value of patients with high-risk cytogenetics (n=25) was 6329 (352-44409), and the median MESF value of patients with standard-risk cytogenetics (n=3) was 2591 (766-4560)
.
FcRH5 expression seems to be roughly equivalent in patients with or without 1q21 gain, t(4;14), and del(17p)
.
No patient with t(14;16) has been detected so far
.
The conclusions of the study are consistent with the previously reported data
.
FcRH5 expression was observed on the myeloma cells of all biomarker-evaluable patients at baseline .
In the patients evaluated so far, no correlation between Cevostamab treatment response and baseline FcRH5 expression levels has been observed
.
FcRH5 expression does not seem to be affected by the number or type of previous treatment lines, including anti-BCMA treatment
.
Patients with high-risk cytogenetic abnormalities may have elevated baseline FcRH5 expression, although additional data are needed to determine this relationship
.
The above data further confirms that FcRH5 is a promising new target in the treatment of multiple myeloma
.
References: 1.
Laubach et al.
Leukemia 2016;30:1005–17; 2.
Ise et al.
Leukemia 2007;21:169–74; 3.
Polson et al.
Int Immunol 2006;18:1363–73; 4 .
Li et al.
Cancer Cell 2017;31:383–95;5.
Cohen et al.
ASH 2020.
Stamp "read the original text", we make progress together
This activates T cells to kill myeloma cells
.
At the 2020 ASH Annual Meeting (#292, #3213), Roche announced for the first time that Cevostamab has shown encouraging activity in multi-line treatment of patients with relapsed/refractory multiple myeloma (RRMM) (GO39775, phase I clinical trial) )
.
The relevant results of the study (EHA-EP965) will be updated again at this EHA annual meeting
.
Research background Almost all MM patients will eventually relapse after initial treatment or salvage treatment1, and there is still a need to study new targets and treatment methods
.
FcRH5 is a type I membrane protein containing an Ig domain and is only expressed in the B cell lineage 2-4
.
The FcRH5 gene is located near the chromosomal breakpoint in 1q21.
4.
Previous studies have shown that the expression rate of FcRH5 on myeloma cells is close to 100%, and the expression rate on myeloma cells is higher than that of normal B cells4
.
Cevostamab is an IgG-based humanized bispecific antibody that binds to the proximal membrane domain of FcRH5 on myeloma cells and CD3 on T cells4
.
Double binding promotes T cell activation and effectively kills myeloma cells4
.
Preliminary data in the dose escalation phase of the ongoing phase I study (GO39775; NCT03275103) indicate that cevostamab monotherapy has controllable toxicity and promising activity in patients with advanced RRMM5
.
In the current analysis, we analyzed the relationship between baseline FcRH5 expression and baseline patient disease characteristics in the GO39775 study, as well as the relationship between baseline FcRH5 expression and response to Cevostamab treatment
.
01 Mainly included in the standard RRMM that is invalid or intolerant to existing treatments; ECOG 0-1; those who have previously received chimeric antigen receptor T cells (CAR-T), bispecific antibodies or antibody-drug conjugates (ADC) Patients can be included in 02Cevostamab dosage and usage (see figure below) Q3W IV, to disease progression or intolerance, the current maximum of 17 cycles is to reduce cytokine release syndrome (CRS), the first cycle (C1) uses a single fraction Step-by-step administration, preventive use of acetaminophen, diphenhydramine, and corticosteroids; only C1 requires hospitalization infusion 03 Primary endpoint of the study: safety and tolerability (MTD, DLTs), phase II recommended dose (RP2D) Secondary endpoint: Expression of the biomarker FcRH5, an activity, pharmacodynamic and pharmacokinetic biomarker, on myeloma cells by flow cytometry and a molecule expressed as an equivalent soluble fluorescent dye (MESF) before treatment with Cevostatab The collected bone marrow aspirate was evaluated
.
The expression of FcRH5 was analyzed hierarchically according to the number of previous treatment lines, treatment types, and cytogenetic abnormalities
.
Cytogenetic abnormalities refer to high-risk (one or more of the following abnormalities: 1q21 gain, t(4;14), t(14;16)), or del(17p)) and standard risk cytogenetics
.
At the end of the study results data (August 18, 2020), 53 patients were enrolled in the study, with a median age of 62 years (33-80 years), a median number of treatment lines (2-15), and 100% had received PIs Treatment, 100% received IMiDs treatment, 81% received anti-CD38 monoclonal antibody (anti-CD38 mAb) treatment, 72% of the patients were refractory to 3 drugs (≥1 PI, ≥1 IMiD, ≥1 anti-CD38 mAb), 94% of patients did not respond to the last treatment
.
28 out of 53 patients had cytogenetic high-risk markers (high-risk genetics, including: 1q21, t(4;14), t(14;16) or del(17p))
.
The ORR in the population ≥ 3.
6/20 mg was 53%, and the ORR was at the active dose level and above, and was stratified according to the number of previous treatment lines to maintain a consistent level
.
In all patients with evaluable biomarkers, FcRH5 expression on myeloma cells was observed; no significant relationship between the response to Cevostamab and the baseline FcRH5 expression level was observed at the active dose level
.
FcRH5 expression does not seem to be affected by the number of previous treatment lines and treatments.
FcRH5 expression may increase in patients with cytogenetic abnormalities, but more data are still needed for further confirmation
.
Among the patients whose biomarkers can be evaluated, 28 can provide cytogenetic information, of which 25 are high-risk and 3 are standard risk
.
The MESF fluorescence value was 8839 (2137-32381, n=9) in patients with two cytogenetic abnormalities, and 5379 (352-44409, n=16) in patients with one cytogenetic abnormality.
The number of patients with abnormal cytogenetics was 2591 (766-4560, n=3)
.
The median MESF value of patients with high-risk cytogenetics (n=25) was 6329 (352-44409), and the median MESF value of patients with standard-risk cytogenetics (n=3) was 2591 (766-4560)
.
FcRH5 expression seems to be roughly equivalent in patients with or without 1q21 gain, t(4;14), and del(17p)
.
No patient with t(14;16) has been detected so far
.
The conclusions of the study are consistent with the previously reported data
.
FcRH5 expression was observed on the myeloma cells of all biomarker-evaluable patients at baseline .
In the patients evaluated so far, no correlation between Cevostamab treatment response and baseline FcRH5 expression levels has been observed
.
FcRH5 expression does not seem to be affected by the number or type of previous treatment lines, including anti-BCMA treatment
.
Patients with high-risk cytogenetic abnormalities may have elevated baseline FcRH5 expression, although additional data are needed to determine this relationship
.
The above data further confirms that FcRH5 is a promising new target in the treatment of multiple myeloma
.
References: 1.
Laubach et al.
Leukemia 2016;30:1005–17; 2.
Ise et al.
Leukemia 2007;21:169–74; 3.
Polson et al.
Int Immunol 2006;18:1363–73; 4 .
Li et al.
Cancer Cell 2017;31:383–95;5.
Cohen et al.
ASH 2020.
Stamp "read the original text", we make progress together
